maytansine and Wilms-Tumor

The cell-surface glycoprotein CD56 has three major isoforms that play important roles in cell adhesion and signaling, which may promote cell proliferation, differentiation, survival, or migration. It is an important molecule in normal kidney development and acts as a key marker in Wilms tumor stem and progenitor cells. Here, we review the structural and genetic features of the CD56 glycoprotein, and summarize its roles in the normal versus diseased metanephric blastema. We discuss areas of CD56-related research that may complement or improve existing Wilms tumor treatment strategies, including the antibody-drug conjugate lorvotuzumab mertansine that binds to CD56.

Topics: Antibodies, Monoclonal; CD56 Antigen; Cell Adhesion; Cell Differentiation; Cell Movement; Cell Proliferation; Cell Survival; Glycoproteins; Humans; Kidney; Maytansine; Protein Binding; Protein Domains; Receptor, Fibroblast Growth Factor, Type 1; Signal Transduction; Wilms Tumor

Lorvotuzumab mertansine (IMGN901) is an antibody-drug conjugate linking an antimitotic agent (DM1) to an anti-CD56 antibody (lorvotuzumab). Preclinical efficacy has been noted in Wilms tumor, rhabdomyosarcoma, and neuroblastoma. Synovial sarcoma, malignant peripheral nerve sheath tumor (MPNST), and pleuropulmonary blastoma also express CD56. A phase 2 trial of lorvotuzumab mertansine was conducted to assess its efficacy, recommended phase 2 dose, and toxicities.. Eligible patients had relapsed after or progressed on standard therapy for their tumor type. Lorvotuzumab mertansine (110 mg/m. Sixty-two patients enrolled. The median age was 14.3 years (range, 2.8-29.9 years); 35 were male. Diagnoses included Wilms tumor (n = 17), rhabdomyosarcoma (n = 17), neuroblastoma (n = 12), synovial sarcoma (n = 10), MPNST (n = 5), and pleuropulmonary blastoma (n = 1). Five patients experienced 9 dose-limiting toxicities: hyperglycemia (n = 1), colonic fistula (n = 1) with perforation (n = 1), nausea (n = 1) with vomiting (n = 1), increased alanine aminotransferase in cycle 1 (n = 2), and increased alanine aminotransferase in cycle 2 (n = 1) with increased aspartate aminotransferase (n = 1). Non-dose-limiting toxicities (grade 3 or higher) attributed to lorvotuzumab mertansine were rare. The median values of the maximum concentration, half-life, and area under the curve from zero to infinity for DM1 were 0.87 µg/mL, 35 hours, and 27.9 µg/mL h, respectively. Peripheral blood CD56+ leukocytes decreased by 71.9% on day 8. One patient with rhabdomyosarcoma had a partial response, and 1 patient with synovial sarcoma achieved a delayed complete response.. Lorvotuzumab mertansine (110 mg/m

Topics: Adolescent; Adult; Antibodies, Monoclonal; Area Under Curve; CD56 Antigen; Child; Child, Preschool; Female; Humans; Male; Maximum Tolerated Dose; Maytansine; Neuroblastoma; Neurofibrosarcoma; Pulmonary Blastoma; Rhabdomyosarcoma; Sarcoma, Synovial; Survival Analysis; Treatment Outcome; Wilms Tumor; Young Adult

There are considerable differences in tumour biology between adult and paediatric cancers. The existence of cancer initiating cells/cancer stem cells (CIC/CSC) in paediatric solid tumours is currently unclear. Here, we show the successful propagation of primary human Wilms' tumour (WT), a common paediatric renal malignancy, in immunodeficient mice, demonstrating the presence of a population of highly proliferative CIC/CSCs capable of serial xenograft initiation. Cell sorting and limiting dilution transplantation analysis of xenograft cells identified WT CSCs that harbour a primitive undifferentiated-NCAM1 expressing-"blastema" phenotype, including a capacity to expand and differentiate into the mature renal-like cell types observed in the primary tumour. WT CSCs, which can be further enriched by aldehyde dehydrogenase activity, overexpressed renal stemness and genes linked to poor patient prognosis, showed preferential protein expression of phosphorylated PKB/Akt and strong reduction of the miR-200 family. Complete eradication of WT in multiple xenograft models was achieved with a human NCAM antibody drug conjugate. The existence of CIC/CSCs in WT provides new therapeutic targets.

Topics: AC133 Antigen; Aldehyde Dehydrogenase; Aldehyde Dehydrogenase 1 Family; Animals; Antibodies, Monoclonal; Antigens, CD; CD56 Antigen; Cell Differentiation; Cell Proliferation; Cell Separation; Gene Expression; Glycoproteins; Humans; Kidney Neoplasms; Maytansine; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells; Peptides; Retinal Dehydrogenase; Tumor Cells, Cultured; Tumor Stem Cell Assay; Wilms Tumor; Xenograft Model Antitumor Assays